Phase 1 pilot study of e-mail support for people with long term conditions using the Internet.

BACKGROUND: Use of the Internet for people with Long Term Conditions (LTCs) can have a positive effect on knowledge, social support, behavioural and clinical outcomes, yet there is concern that a 'digital divide' prevents some patients from benefitting. While some patients do not have access to the Internet, others that do may still lack expertise or the confidence to make full use of it. The aim of this pilot study was to develop an intervention and test methods for a definitive randomised controlled trial (RCT) of anonymous personal online email support for patients in this latter group. METHODS: Recruitment success was evaluated by the number and appropriateness of participants recruited. A personalised e-health support intervention was developed. The provisional primary outcome was the extent to which the Internet affected the participants' confidence in dealing with their LTC. Primary outcome, seven process measures and two secondary outcomes measures were evaluated for completeness of data and sensitivity to detect changes. RESULTS: Thirty nine participants were recruited, 29 after personally receiving a leaflet, seven via email advertising, and three via leaflets left in waiting areas. Most participants (61%) were aged over 60. The majority (21/38) rated themselves as experienced Internet users although only 5/38 had used discussion forums for their LTC. Piloting the intervention identified support needed as: (i) technical help with some websites, (ii) advice about issues such as anonymity, (iii) help in judging information quality, (iv) identification of relevant information (via 'Information Prescriptions'), (v) motivational support to try new sites. Attrition was fairly high: 20/39 completed follow up questionnaires. Three process measures showed ceiling effects and two had too many missing values to be useable. CONCLUSION: E-health support is a promising way of addressing the problems faced by older generation e-health seekers. Face-to-face leaflet distribution recruited sufficient numbers but additional locations other than hospital should be tried to recruit Internet novices with LTCs. An RCT is feasible and necessary to evaluate the potential benefits of anonymous email support. Our methods could be used by other researchers studying Internet use by people with LTCs

The chemistry of quartz in granitic pegmatites of southern Norway: Petrogenetic and economic implications

This is the author accepted manuscript. The final version is available from Society of Economic Geologists via the DOI in this record.Trace element concentrations in quartz from 188 granitic pegmatites in the Froland and Evje-Iveland pegmatite fields, southern Norway, have been determined to establish exploration targets for high-purity quartz and to gain a better understanding of the genesis of pegmatites hosting these deposits. Both pegmatite fields were formed during the Sveconorwegian (Grenvillian) orogeny (1145-900 Ma) at the western margin of the Fennoscandian Shield. In situ raster analyses within single quartz crystals were undertaken by laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS); spot size 75 μm) to assess levels of lattice-bound impurities, rather than mineral and fluid inclusions that are relatively easily removed during high-purity quartz processing. Quartz in the Froland pegmatites has relatively pure and homogeneous compositions containing 46 ± 24 μgg-1Al, 8 ± 3 μgg-1Ti, 1.4 ± 0.8 μgg-1Ge, and 11 ± 7 μgg-1Li. The Ti-in-quartz geothermobarometer gives an average pegmatite crystallization temperature of 537° ± 39°C. Temperature estimates are highest along the northwestern margin of the pegmatite field (>550°C), whereas the most differentiated pegmatites occur toward the northeast. The area of greatest economic potential for high-purity quartz lies just north of the central part of the field where individual pegmatites contain >1 million metric tons (Mt) quartz with low average trace element contents of 67 ± 11 μgg-1. From mineral-chemical criteria, and a range of other geologic factors, we propose that pegmatite melts in the Froland field were generated by fluid-present crustal melting at about 1060 Ma, in zones of localized high-strain deformation during progressive thrusting along the Porsgrunn-Kristiansand fault zone. Quartz in the Evje-Iveland pegmatites has more variable compositions with 69 ± 57 μgg-1Al, 19 ± 11 μgg-1Ti, 2.3 ± 1.8 μgg-1Ge, and 7 ± 5 μgg-1Li. From its Ti content, it crystallized at temperatures of 613° ± 70°C. The regional spatial distribution of Ti-in-quartz temperatures appears irregular mainly due to the scattered distributions of chemical evolved pegmatites with "amazonite"-"cleavelandite" replacement zones, which show crystallization temperatures down to 442°C. Quartz from the Evje-Iveland pegmatites is unlikely to be of current economic interest due to its moderate to high trace element contents, heterogeneous chemistry, and low volume. The Evje-Iveland pegmatites show no apparent genetic link to a granite intrusion; instead they probably formed as a result of partial melting at the depth of their amphibolite country rocks at around 910 Ma. This is related to a regional low-pressure/high-temperature metamorphic event at about 930 to 920 Ma.Geological Survey of Norway in Trondhei

NLL′{'} resummation of jet mass

Starting from a factorization theorem in effective field theory, we present resummed results for two non-global observables: the invariant-mass distribution of jets and the energy distribution outside jets. Our results include the full next-to-leading-order corrections to the hard, jet and soft functions and are implemented in a parton-shower framework which generates the renormalization-group running in the effective theory. The inclusion of these matching corrections leads to an improved description of the data and reduced theoretical uncertainties. They will have to be combined with two-loop running in the future, but our results are an important first step towards the higher-logarithmic resummation of non-global observables.Comment: 32 pages, 12 figures. v2: journal versio

Protein disulfide-isomerase interacts with a substrate protein at all stages along its folding pathway

In contrast to molecular chaperones that couple protein folding to ATP hydrolysis, protein disulfide-isomerase (PDI) catalyzes protein folding coupled to formation of disulfide bonds (oxidative folding). However, we do not know how PDI distinguishes folded, partly-folded and unfolded protein substrates. As a model intermediate in an oxidative folding pathway, we prepared a two-disulfide mutant of basic pancreatic trypsin inhibitor (BPTI) and showed by NMR that it is partly-folded and highly dynamic. NMR studies show that it binds to PDI at the same site that binds peptide ligands, with rapid binding and dissociation kinetics; surface plasmon resonance shows its interaction with PDI has a Kd of ca. 10−5 M. For comparison, we characterized the interactions of PDI with native BPTI and fully-unfolded BPTI. Interestingly, PDI does bind native BPTI, but binding is quantitatively weaker than with partly-folded and unfolded BPTI. Hence PDI recognizes and binds substrates via permanently or transiently unfolded regions. This is the first study of PDI's interaction with a partly-folded protein, and the first to analyze this folding catalyst's changing interactions with substrates along an oxidative folding pathway. We have identified key features that make PDI an effective catalyst of oxidative protein folding – differential affinity, rapid ligand exchange and conformational flexibility

Interest in healthy living outweighs presumed cultural norms for obesity for Ghanaian women

BACKGROUND: Cultural norms indicate that obesity reflects increased wealth and prosperity. Yet obesity is linked to serious medical illnesses. The purpose of this study was to determine if Ghanaian women would change their body image if it meant a healthier life. METHODS: A questionnaire was administered to 305 Ghanaian women waiting for clinic appointments at Korle Bu Teaching Hospital, Accra Ghana. This survey included questions on current health, selection of figural stimuli, decision making on health and social determinants and 5 questions on self-perception of health from SF-36. Anthropometric measures were taken and body mass index calculated. Women were also provided with health related information at the conclusion of the interview. RESULTS: The majority of all women surveyed would reduce their current body image if it meant that they would have an overall healthier life and reduce the risks of obesity-linked illnesses and complications. Currently obese women were significantly more likely than non-obese women to reduce their body image to reduce the risk of hypertension (OR 2.03 [1.64 – 2.51],<0.001); cardiovascular accident (OR 1.96 [1.61 – 2.38],<0.001); diabetes (OR 2.00 [1.63 – 2.44],<0.001); myocardial infarction (OR 2.27 [1.80 – 2.86],<0.001); if requested by a spouse(OR 2.64 [1.98 – 3.52],<0.001); and to improve overall health (OR 1.95 [1.60 – 2.37], <0.001). There was no association with current body image and responses to SF-36. The decision to select a new body image was not influenced by education, income, marital status or parity. Age 50 years old and less was significantly associated with the body image size reduction to reduce the risk of hypertension, diabetes, and a cardiovascular accident. CONCLUSION: The Ghanaian women interviewed in this study are interested in living a healthy life and are willing to reduce their body size to reduce the risk of obesity-linked illnesses. The target group for any interventional studies and measures to reduce obesity appears to be women age 50 and younger

Priming with recombinant auxotrophic BCG expressing HIV-1 Gag, RT and Gp120 and boosting with recombinant MVA induces a robust T cell response in mice

In previous studies we have shown that a pantothenate auxotroph of Myocbacterium bovis BCG (BCGΔ panCD ) expressing HIV-1 subtype C Gag induced Gag-specific immune responses in mice and Chacma baboons after prime-boost immunization in combination with matched rMVA and VLP vaccines respectively. In this study recombinant BCG (rBCG) expressing HIV-1 subtype C reverse transcriptase and a truncated envelope were constructed using both the wild type BCG Pasteur strain as a vector and the pantothenate auxotroph. Mice were primed with rBCG expressing Gag and RT and boosted with a recombinant MVA, expressing a polyprotein of Gag, RT, Tat and Nef (SAAVI MVA-C). Priming with rBCGΔ panCD expressing Gag or RT rather than the wild type rBCG expressing Gag or RT resulted in higher frequencies of total HIV-specific CD8 + T cells and increased numbers of T cells specific to the subdominant Gag and RT epitopes. Increasing the dose of rBCG from 10 5 cfu to 10 7 cfu also led to an increase in the frequency of responses to subdominant HIV epitopes. A mix of the individual rBCGΔ panCD vaccines expressing either Gag, RT or the truncated Env primed the immune system for a boost with SAAVI MVA-C and generated five-fold higher numbers of HIV-specific IFN-γ-spot forming cells than mice primed with rBCGΔ panCD containing an empty vector control. Priming with the individual rBCGΔ panCD vaccines or the mix and boosting with SAAVI MVA-C also resulted in the generation of HIV-specific CD4 + and CD8 + T cells producing IFN-γ and TNF-α and CD4 + cells producing IL-2. The rBCG vaccines tested in this study were able to prime the immune system for a boost with rMVA expressing matching antigens, inducing robust, HIV-specific T cell responses to both dominant and subdominant epitopes in the individual proteins when used as individual vaccines or in a mix

Climate-carbon cycle uncertainties and the Paris Agreement

The Paris Agreement aims to address the gap between existing climate policies and policies consistent with ‘holding the increase in global average temperature to well below 2C’. The feasibility of meeting the target has been questioned both in terms of the possible requirement for negative emissions, and ongoing debate on the sensitivity of the climate-carbon cycle system. Using a sequence of ensembles of a fully dynamic three-dimensional climate-carbon cycle model, forced by emissions from an integrated assessment model of regional-level climate policy, economy, and technological transformation, we show that a reasonable interpretation of the Paris Agreement is still technically achievable. Specifically, limiting peak (decadal) warming to less than 1.7°C, or end-century warming to less than 1.54°C, occurs in 50% of our simulations in a policy scenario without net negative emissions or excessive stringency in any policy domain. We evaluate two mitigation scenarios, with 200 GTC and 307 GTC post-2017 emissions, quantifying spatio-temporal variability of warming, precipitation, ocean acidification and marine productivity. Under rapid decarbonisation decadal variability dominates the mean response in critical regions, with significant implications for decision making, demanding impact methodologies that address non-linear spatio-temporal responses. Ignoring carbon-cycle feedback uncertainties (explaining 47% of peak warming uncertainty) becomes unreasonable under strong mitigation conditions.We acknowledge C-EERNG and Cambridge Econometrics for support, and funding from EPSRC (to J.-F.M., fellowship number EP/ K007254/1); the Newton Fund (to J.-F.M., P.S. and J.E.V., EPSRC grant number EP/N002504/1 and ESRC grant number ES/N013174/1), NERC (to N.R.E., P.H. and H.P., grant number NE/P015093/1), CONICYT (to P.S.), the Philomathia Foundation (to J.E.V.) and Horizon 2020 (to H.E.P. and J.-F.M., the Sim4Nexus project)

Effective nebulization of interferon-γ using a novel vibrating mesh.

BACKGROUND: Interferon gamma (IFN-γ) is a clinically relevant immunomodulatory cytokine that has demonstrated significant potential in the treatment and management of respiratory diseases such as tuberculosis and pulmonary fibrosis. As with all large biomolecules, clinical translation is dependent on effective delivery to the disease site and delivery of IFN-γ as an aerosol offers a logical means of drug targeting. Effective localization is often hampered by instability and a lack of safe and efficient delivery systems. The present study sought to determine how effectively IFN-γ can be nebulized using two types of vibrating mesh nebulizer, each with differing mesh architectures, and to investigate the comparative efficiency of delivery of therapeutically active IFN-γ to the lungs. METHODS: Nebulization of IFN-γ was carried out using two different Aerogen vibrating mesh technologies with differing mesh architectures. These technologies represent both a standard commercially available mesh type (Aerogen Solo®) and a new iteration mesh (Photo-defined aperture plate (PDAP®). Extensive aerosol studies (aerosol output and droplet analysis, non-invasive and invasive aerosol therapy) were conducted in line with regulatory requirements and characterization of the stability and bioactivity of the IFN-γ post-nebulization was confirmed using SDS-PAGE and stimulation of Human C-X-C motif chemokine 10 (CXCL 10) also known as IFN-γ-induced protein 10KDa (IP 10) expression from THP-1 derived macrophages (THP-1 cells). RESULTS: Aerosol characterization studies indicated that a significant and reproducible dose of aerosolized IFN-γ can be delivered using both vibrating mesh technologies. Nebulization using both devices resulted in an emitted dose of at least 93% (100% dose minus residual volume) for IFN-γ. Characterization of aerosolized IFN-γ indicated that the PDAP was capable of generating droplets with a significantly lower mass median aerodynamic diameter (MMAD) with values of 2.79 ± 0.29 μm and 4.39 ± 0.25 μm for the PDAP and Solo respectively. The volume median diameters (VMD) of aerosolized IFN-γ corroborated this with VMDs of 2.33 ± 0.02 μm for the PDAP and 4.30 ± 0.02 μm for the Solo. SDS-PAGE gels indicated that IFN-γ remains stable after nebulization by both devices and this was confirmed by bioactivity studies using a THP-1 cell model in which an alveolar macrophage response to IFN-γ was determined. IFN-γ nebulized by the PDAP and Solo devices had no significant effect on the key inflammatory biomarker cytokine IP-10 release from this model in comparison to non-nebulized controls. Here we demonstrate that it is possible to combine IFN-γ with vibrating mesh nebulizer devices and facilitate effective aerosolisation with minimal impact on IFN-γ structure or bioactivity. CONCLUSIONS: It is possible to nebulize IFN-γ effectively with vibrating mesh nebulizer devices without compromising its stability. The PDAP allows for generation of IFN-γ aerosols with improved aerodynamic properties thereby increasing its potential efficiency for lower respiratory tract deposition over current technology, whilst maintaining the integrity and bioactivity of IFN-γ. This delivery modality therefore offers a rational means of facilitating the clinical translation of inhaled IFN-γ